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Globally, cryptococcal meningitis is a leading cause of mortality among people with AIDS, despite the availability of effective amphotericin B–based therapy. In this trial in sub-Saharan Africa, the efficacy of two simpler treatment regimens was assessed.

The treatment of visceral leishmaniasis (kala-azar) often requires prolonged therapy. In this open-label, randomized study involving more than 400 patients in Bihar, India, a single infusion of liposomal amphotericin B was noninferior to a regimen of 15 alternate-day infusions of conventional amphotericin B deoxycholate. In patients in Bihar, India, a single infusion of liposomal amphotericin B was noninferior to a regimen of 15 alternate-day infusions of conventional amphotericin B deoxycholate. Some 90% of patients with visceral leishmaniasis (kala-azar) in India and nearly 50% of patients worldwide live in the northeastern Indian state of Bihar. 1 In Bihar, treatment with liposomal amphotericin B is effective in regimens as brief as 5 days, 1 – 3 offering a remedy for the principal drawback of all other antileishmanial agents: a prolonged duration of treatment. 1 , 4 However, when such a regimen of liposomal amphotericin B was abbreviated still further, to a single infusion of 5 or 7.5 mg per kilogram of body weight, the efficacy of the drug (90 to 91% 4 – 6 ) did not reach the . . .

Background Cryptococcal meningitis (CM) is a major cause of mortality in HIV programmes in Africa despite increasing access to antiretroviral therapy (ART). Mortality is driven in part by limited availability of amphotericin-based treatment, drug-induced toxicities of amphotericin B deoxycholate and prolonged hospital admissions. A single, high-dose of liposomal amphotericin (L-AmB, Ambisome) on a fluconazole backbone has been reported as non-inferior to 14 days of standard dose L-AmB in reducing fungal burden. This trial examines whether single, high-dose L-AmB given with high-dose fluconazole and flucytosine is non-inferior to a seven-day course of amphotericin B deoxycholate plus flucytosine (the current World Health Organization [WHO] recommended treatment regimen). Methods An open-label phase III randomised controlled non-inferiority trial conducted in five countries in sub-Saharan Africa: Botswana, Malawi, South Africa, Uganda and Zimbabwe. The trial will compare CM induction therapy with (1) a single dose (10 mg/kg) of L-AmB given with 14 days of fluconazole (1200 mg/day) and flucytosine (100 mg/kg/day) to (2) seven days amphotericin B deoxycholate (1 mg/kg/day) given alongside seven days of flucytosine (100 mg/kg/day) followed by seven days of fluconazole (1200 mg/day). The primary endpoint is all-cause mortality at ten weeks with a non-inferiority margin of 10% and 90% power. Secondary endpoints are early fungicidal activity, proportion of grade III/IV adverse events, pharmacokinetic parameters and pharmacokinetic/pharmacodynamic associations, health service costs, all-cause mortality within the first two and four weeks, all-cause mortality within the first ten weeks (superiority analysis) and rates of CM relapse, immune reconstitution inflammatory syndrome and disability at ten weeks. A total of 850 patients aged ≥ 18 years with a first episode of HIV-associated CM will be enrolled (425 randomised to each arm). All patients will be followed for 16 weeks. All patients will receive consolidation therapy with fluconazole 800 mg/day to complete ten weeks of treatment, followed by fluconazole maintenance and ART as per local guidance. Discussion A safe, sustainable and easy to administer regimen of L-AmB that is non-inferior to seven days of daily amphotericin B deoxycholate therapy may reduce the number of adverse events seen in patients treated with amphotericin B deoxycholate and shorten hospital admissions, providing a highly favourable and implementable alternative to the current WHO recommended first-line treatment. Trial registration ISRCTN, ISRCTN72509687 . Registered on 13 July 2017.

In Southeast Asia, treatment is recommended for all patients with post-kala-azar dermal leishmaniasis (PKDL). Adherence to the first-line regimen, twelve weeks of miltefosine (MF), is low and ocular toxicity has been observed with this exposure period. We assessed the safety and efficacy of two shorter-course treatments: liposomal amphotericin B (LAmB) alone and combined with MF. An open-label, phase II, randomized, parallel-arm, non-comparative trial was conducted in patients with parasitologically confirmed PKDL, 6 to ≤60 years. Patients were assigned to 20 mg/kg LAmB (total dose, in five injections over 15 days) alone or combined with allometric MF (3 weeks). The primary endpoint was definitive cure at 12 months, defined as complete resolution of papular and nodular lesions and >80% re-pigmentation of macular lesions. Definitive cure at 24 months was a secondary efficacy endpoint. 118/126 patients completed the trial. Definitive cure at 12 months was observed in 29% (18/63) patients receiving LAmB and 30% (19/63) receiving LAmB/MF (mITT), increasing to 58% and 66%, respectively, at 24 months. Most lesions had resolved/improved at 12 and 24 months for patients receiving LAmB (90%, 83%) and LAmB/MF (85%, 88%) by qualitative assessment. One death, unrelated to study drugs, was reported; no study drug-related serious adverse events were observed. The most frequent adverse drug reactions were MF-related vomiting and nausea, and LAmB-related hypokalaemia and infusion reactions. Most adverse events were mild; no ocular adverse events occurred. Both regimens are suitably safe and efficacious alternatives to long-course MF for PKDL in South Asia. CTRI/2017/04/008421.

Fungal keratitis (FK), a major cause of blindness, remains challenging to treat due to poor drug penetration and antifungal resistance. Amphotericin-B (AmB), a water-insoluble and low-permeability, necessitates innovative delivery systems to improve its therapeutic efficacy. AmB was encapsulated within oleosomes (Ole) prepared using the ethanol injection method, using phosphatidylcholine (Lipoid S100) and sodium oleate, resulting in nanosized spherical globules. The optimized Ole were characterized, then the selected Ole were incorporated into sodium polyacrylate/PEG/chitosan-based microneedles (AmB-Ole/MNs) to improve ocular delivery by creating transient microchannels on the eye surface. The optimized Ole showed a droplet size of (175 ± 0.78 nm), polydispersity index of (0.33 ± 0.04), zeta potential of (31 ± 0.43 mV), high entrapment efficiency (91±0.63%), and improved stability, bioavailability, and controlled drug release. The AmB-Ole/MNs system increases corneal penetration and contact time via transient microchannels in the eye surface, achieving sustained drug delivery over 72 hours with 70% ex vivo permeation over 80 hours compared to AmB. In vitro antifungal activity and histopathological examination showed that the AmB-Ole/MNs system has potent biofilm disruption (>90%) and 27 mm and 32 mm zones of inhibition against and Aspergillus niger, respectively. The Cytotoxicity test showed reduced AmB toxicity with biocompatibility and in vivo , ocular tolerance by targeting TLR4/NLRP3 pathways and histopathological studies. The AmB-Ole/MNs system as an innovative ocular delivery platform for fungal keratitis offers sustained drug release, enhanced permeation, potent antifungal activity, and reduced toxicity. AmB-Ole/MNs showed promise for ocular AmB delivery for FK.

Determining the best therapy for HIV-associated cryptococcal meningitis in resource-poor settings is controversial. In this trial in Vietnam, initial therapy with amphotericin B with flucytosine had better outcomes than amphotericin B alone or with fluconazole. There are approximately 1 million cases of cryptococcal meningitis annually and 625,000 deaths. 1 Treatment guidelines recommend induction therapy with amphotericin B deoxycholate (0.7 to 1 mg per kilogram of body weight per day) and flucytosine (100 mg per kilogram per day). 2 However, this treatment has not been shown to reduce mortality, as compared with amphotericin B monotherapy. 2 , 3 Flucytosine is frequently unavailable where the disease burden is greatest, and concerns about cost and side effects have limited its use in resource-poor settings. 4 Fluconazole is readily available, is associated with low rates of adverse events, and has good penetration into cerebrospinal . . .

Talaromyces marneffei is a dimorphic fungus that causes substantial disease in Asia, especially among persons infected with the human immunodeficiency virus. In this randomized, controlled trial, initial therapy with amphotericin B was found to be superior to itraconazole. The dimorphic fungus Talaromyces (previously Penicillium ) marneffei causes a life-threatening mycosis in immunocompromised persons living in or traveling to Southeast Asia, China, and India. 1 Talaromycosis (previously penicilliosis) is a major cause of human immunodeficiency virus (HIV)–related death; its prevalence is surpassed only by the prevalence of tuberculosis and cryptococcosis, 2 and it leads to 4 to 15% of HIV-related hospital admissions in regions in which the disease is endemic. 3 – 7 Talaromycosis is increasingly diagnosed among patients who are not infected with HIV but who have other immunodeficiency conditions 8 and is reported to be the second most common cause of all . . .

Chitosan nanoparticles have gained attention as drug delivery systems (DDS) in the medical field as they are both biodegradable and biocompatible with reported antimicrobial and anti-leishmanial activities. We investigated the application of chitosan nanoparticles as a DDS for the treatment of cutaneous leishmaniasis (CL) by preparing two types of chitosan nanoparticles: positively charged with tripolyphosphate sodium (TPP) and negatively charged with dextran sulphate. Amphotericin B (AmB) was incorporated into these nanoparticles. Both types of AmB-loaded nanoparticles demonstrated in vitro activity against Leishmania major intracellular amastigotes, with similar activity to unencapsulated AmB, but with a significant lower toxicity to KB-cells and red blood cells. In murine models of CL caused by L. major, intravenous administration of AmB-loaded chitosan-TPP nanoparticles (Size = 69 ± 8 nm, Zeta potential = 25.5 ± 1 mV, 5 mg/kg/for 10 days on alternate days) showed a significantly higher efficacy than AmBisome® (10 mg/kg/for 10 days on alternate days) in terms of reduction of lesion size and parasite load (measured by both bioluminescence and qPCR). Poor drug permeation into and through mouse skin, using Franz diffusion cells, showed that AmB-loaded chitosan nanoparticles are not appropriate candidates for topical treatment of CL.

COVID-19 patients often develop serious fungal infections like Aspergillosis, Candidiasis, and Mucormycosis, which are treated with antifungal drugs like Amphotericin B, Posaconazole, and Isavuconazole. However, these treatments are often insufficient, leading researchers to explore drug combinations and analogs. In theoretical chemistry, a chemical molecule is converted into an isomorphic molecular graph, represented as G (V, E) by considering atom set V as vertices and bond set E as edges. Quantitative structure–activity/property/toxicity relationships (QSAR, QSPR, QSTR) modelling is a widely recognized discipline that correlates physicochemical and molecular descriptors with a drug’s bioactivity to predict its standard pharmacological properties. In this article, the aforementioned drugs, as well as some Amphotericin B analogs, with their properties, are considered for QSPR/QSTR analysis. The QSPR/QSTR analysis is carried out using linear regression between the computed topological indices (based on degree and neighbourhood degree sum) and pharmacokinetic (ADMET) and toxicity properties (LD 50 ) of these drugs. The analysis reveals a strong correlation between the topological indices and the pharmacokinetic and toxicity properties of the drugs and their analogs. These insights are crucial for advancing more effective antifungal treatments, especially for COVID-19-related infections.

This multinational, double-blind trial compared caspofungin, an echinocandin, with liposomal amphotericin B as empirical antifungal therapy in 1095 patients with persistent fever and neutropenia. Caspofungin was as efficacious as the standard therapy and was better tolerated, with less nephrotoxicity and fewer drug-related adverse events. This multinational trial compared caspofungin with liposomal amphotericin B. The results support an effective new option for empirical antifungal therapy in high-risk patients. Invasive fungal infections are important causes of illness and death in patients with neutropenia who receive chemotherapy for cancer or who undergo hematopoietic stem-cell transplantation. 1 – 3 Persistent fever in patients with neutropenia who are receiving broad-spectrum antibiotics may be the only clinical indication of an invasive fungal infection. Amphotericin B and its lipid formulations, as well as triazoles (fluconazole, itraconazole, and voriconazole), have been studied as empirical antifungal agents in patients with persistent fever and neutropenia. 4 – 11 However, these agents may be associated with toxicity and adverse drug interactions and have a limited spectrum of activity, erratic bioavailability, unpredictable pharmacokinetics, . . .